Year: 2024
Type: article
Abstract: Understanding neuromodulatory effects of serotonin 2A receptor (5-HT 2A R) agonists with diverse pharmacological profiles is relevant to advancing psychedelic-related drug applications. We performed simultaneous positron emission tomography (PET) and pharmacological magnetic resonance imaging (phMRI) in anesthetized nonhuman primates (NHP; N = 3) to examine partial agonists with varying 5-HT 2A R affinities and selectivity profiles: psilocybin (30, 60, and 90 µg/kg), lisuride (5 µg/kg), and 25CN-NBOH (15 µg/kg). Receptor occupancy was assessed with [ 11 C]MDL-100907 PET, and cerebral blood volume (CBV) changes were measured with phMRI. Mixed partial agonists psilocybin and lisuride evoked biphasic CBV responses, whereas the selective 25CN-NBOH produced monophasic CBV increases. Cortical occupancy for psilocybin plateaued at 60 µg/kg (32%), whereas a lower dose of lisuride (5 µg/kg) resulted in similar occupancy (31%). Administration of 25CN-NBOH resulted in lower occupancy (7%) but larger changes in CBV compared to psilocybin and lisuride. The associations between CBV and 5-HT 2A R occupancy appear linear for lisuride and 25CN-NBOH, but not for psilocybin. We speculate that the temporal and spatial differences in hemodynamic responses of the three agonists could stem from mixed affinity profiles. This work provides an understanding of pharmacological impacts of mixed serotonergic agonists being pursued as therapeutics for psychiatric conditions, offering valuable insights for future drug applications and development strategies.
Language: English
Subfield: Clinical Psychology
Field: Psychology
Domain: Social Sciences
Open Access status: bronze
Funders: Brain and Behavior Research Foundation, Massachusetts General Hospital, Lundbeckfonden, Centre d'Imagerie BioMédicale, H. Lundbeck A/S, National Institutes of Health, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, National Institute on Aging, National Institute on Drug Abuse, National Institute of Biomedical Imaging and Bioengineering, National Center for Research Resources
Awards: G1243485958, G2096213962, Combined MRI/PET Imager for Simultaneous Acquisition of PET/MRI Data, Imaging dopamine receptor adaptations and signaling pathways with combined PET/fMRI, Carbon-11 Radiopharmaceutical Production System, G3169261510, Carbon-11 Automation Equipment for Human PET Radiotracer Production, G3549079774, G5030488558, G578801012, Cyclotron and Radiochemistry, Center for Functional Imaging Technologies, High Resolution PET Camera for Brain Imaging, A Storage Area Network for Structural and Functional Image Analysis, Program to enrich translation and multimodal research in Alzheimers disease and related dementias
OpenAlex ID: W4404864305